SR 48968, A Novel Non-peptide Tachykinin NK-2-Receptor Antagonist, Selectively Inhibits the Non-Cholinergically Mediated Neurogenic Contraction of Guinea-pig Isolated Bronchial Muscle

We have examined the actions of SR 48968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]benzamide), a novel non-peptide tachykinin NK-2-receptor antagonist, on the response evoked by electrical field stimulation or by acetylcholine and neurokinin A on guinea-pig isolated airway smooth muscle. Electrical field stimulation (1-32 Hz, 0.3 ms, 30 V for 20 s) evoked a biphasic response in a frequency-dependent manner, consisting of a cholinergically-mediated fast contraction followed by a non-adrenergically-mediated relaxation in tracheal muscle and by a non-cholinergically-mediated slow contraction in bronchial muscle. SR 48968 (0.01-1 microM) caused a concentration-dependent inhibition of non-cholinergically mediated contraction of bronchial muscle, without significant influence on cholinergically and non-adrenergically-mediated responses. Submaximal contractions of tracheal and bronchial muscles evoked by exogenous neurokinin A (10-300 nM) were markedly inhibited by SR 48968 (0.1-1 microM), but those by exogenous acetylcholine (1-3 microM) were slightly inhibited by the antagonist. The results indicate that in guinea-pig isolated bronchial muscle, SR 48968 selectively inhibited non-cholinergically mediated neurogenic contraction via antagonism of NK-2 receptors.